Summary Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and altered circulating glucocorticoid levels are closely associated with mental health disorders. Corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN) control activation of the HPA axis, and direct stress- and anxiety- associated behaviors. Alterations of the CRH neuron excitatory-inhibitory balance caused by plastic changes in synaptic circuits result in altered HPA activity and shifting circulating glucocorticoids, which can lead to changes in physiological homeostasis and behavioral outputs. Afferent noradrenergic circuits are critical for controlling CRH neuron activity and HPA activation, yet little is known about the mechanism by which norepinephrine (NE) regulates the CRH neurons or its plasticity with stress exposure. Our preliminary findings reveal a novel mechanism of dendritic volume transmission in PVN CRH neurons that is activated by NE and mediated by an astrocytic retrograde relay and gliotransmission to stimulate local excitatory synaptic circuits. We have also found that stress-induced glucocorticoids cause a rapid suppression of the NE activation of the PVN CRH neurons that is mediated by ?1 adrenoreceptor desensitization. This rapid glucocorticoid effect is likely to contribute to the feedback inhibition of the HPA axis, but its specificity to physiological vs. psychological stress inputs and its role in stress-associated behaviors are not known. Here, we will use a combination of patch clamp recordings, live-cell imaging, biochemical analysis, and behavioral testing to address three specific aims. Aim 1 will focus on the pre- and postsynaptic mechanisms in CRH neurons in brain slices that are responsible for ?1 adrenoreceptor-induced neuronal-glial retrograde signaling that activates upstream glutamate circuits. Aim 2 will determine the cellular mechanisms of the stress-induced plasticity of the NE regulation of CRH neuron activity by probing the rapid glucocorticoid regulation of ?1 adrenoreceptor trafficking and signaling. Aim 3 will take an in vivo approach to examine the role of the NE afferents in HPA activation by physiological and psychological inputs, and to study the impact of the stress plasticity of NE regulation of CRH neurons on a core stress behavioral phenotype, anxiety. Together, these studies will fill an important gap in our understanding of the noradrenergic mechanisms of HPA regulation and the stress plasticity of central circuits controlling the CRH neurons and their physiological and behavioral outputs.